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WO2025180349A1 - Solide de composé, son procédé de préparation et son utilisation - Google Patents

Solide de composé, son procédé de préparation et son utilisation

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Publication number
WO2025180349A1
WO2025180349A1 PCT/CN2025/078952 CN2025078952W WO2025180349A1 WO 2025180349 A1 WO2025180349 A1 WO 2025180349A1 CN 2025078952 W CN2025078952 W CN 2025078952W WO 2025180349 A1 WO2025180349 A1 WO 2025180349A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
ray powder
solid form
powder diffraction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/078952
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English (en)
Chinese (zh)
Other versions
WO2025180349A9 (fr
Inventor
周岩锋
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Apeiron Therapeutics Co Ltd
Original Assignee
Shanghai Apeiron Therapeutics Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Publication of WO2025180349A1 publication Critical patent/WO2025180349A1/fr
Publication of WO2025180349A9 publication Critical patent/WO2025180349A9/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to the field of crystal chemistry, and in particular to a solid of (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide.
  • polymorphism refers to the phenomenon of a compound existing in multiple forms and is a significant factor affecting drug quality.
  • a crystal is a solid in which the compound molecules are arranged in a three-dimensional, ordered microstructure, forming a crystalline lattice.
  • An amorphous form is a solid lacking a long-range, ordered structure, formed by the disordered arrangement of the compound molecules within the microstructure.
  • a compound may exist in one or more crystalline forms, but their existence and properties cannot be specifically predicted.
  • the changes in properties caused by different crystalline forms can also improve the final dosage form. For example, such changes can increase solubility and thereby improve bioavailability, or improve the stability of the active ingredient. Or, more surprisingly, increase solubility while maintaining good stability and lower hygroscopicity.
  • a comprehensive study of polymorphism is necessary to obtain a form that meets the pharmaceutical requirements of Compound I.
  • the technical problem to be solved by the present disclosure is to overcome the defect of Compound I lacking a pharmaceutical solid and improve its physical and chemical properties, thereby providing a solid of Compound I, which can be a crystal and/or amorphous form of an anhydrate or solvate.
  • the solid of Compound 1 provided herein is crystalline.
  • the solid form of Compound 1 provided herein is amorphous.
  • the solid of Compound 1 provided herein is an anhydrate.
  • the solid form of Compound 1 provided herein is a solvate, which may also be a hydrate; further, the solvent molecules and Compound 1 may be in a stoichiometric ratio or a non-stoichiometric ratio.
  • Form A a crystal A of Compound 1 (hereinafter referred to as "Form A")
  • Form A has an X-ray powder diffraction pattern substantially as shown in FIG1 using Cu-ka radiation.
  • thermogravimetric analysis/differential scanning calorimetry analysis diagram of Form A is substantially as shown in Figure 2. The results show that Form A loses 0.36% of its mass when heated from 31°C to 120°C, and an endothermic peak begins to appear near 224.0°C.
  • Form A is an anhydrate.
  • the X-ray powder diffraction pattern of the crystalline form A has a diffraction angle 2 ⁇ value of 7.10° ⁇ 0.2°, 8.63° ⁇ 0.2°, 11.55° ⁇ 0.2°, 12.40° ⁇ 0.2°, 14.07° ⁇ 0.2°, 16.01° ⁇ 0.2°, 17.20° ⁇ 0.2°, 17.78° ⁇ 0.2°, 18.20° ⁇ 0.2°, 19.16° ⁇ 0.2°, There are characteristic peaks at any one, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16 of 19.77° ⁇ 0.2°, 20.21° ⁇ 0.2°, 21.43° ⁇ 0.2°, 23.24° ⁇ 0.2°, 24.25° ⁇ 0.2°, and 29.02° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form A has a characteristic peak at a 2 ⁇ value of 16.01° ⁇ 0.2°, and arbitrarily has two characteristic peaks at 2 ⁇ values of 8.63° ⁇ 0.2°, 11.55° ⁇ 0.2°, 17.78° ⁇ 0.2°, 21.43° ⁇ 0.2°, and 23.24° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2 ⁇ values of 8.63° ⁇ 0.2° and 16.01° ⁇ 0.2°, and arbitrarily has one characteristic peak at 2 ⁇ values of 11.55° ⁇ 0.2°, 17.78° ⁇ 0.2°, 21.43° ⁇ 0.2°, and 23.24° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2 ⁇ values of 8.63° ⁇ 0.2°, 16.01° ⁇ 0.2°, and 21.43° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2 ⁇ values of 8.63° ⁇ 0.2°, 16.01° ⁇ 0.2° and 21.43° ⁇ 0.2°, and arbitrarily has one characteristic peak at 2 ⁇ values of 11.55° ⁇ 0.2°, 17.78° ⁇ 0.2° and 23.24° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2 ⁇ values of 8.63° ⁇ 0.2°, 11.55° ⁇ 0.2°, 16.01° ⁇ 0.2°, and 21.43° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at diffraction angles 2 ⁇ of 8.63° ⁇ 0.2°, 11.55° ⁇ 0.2°, 16.01° ⁇ 0.2°, 17.78° ⁇ 0.2°, 21.43° ⁇ 0.2°, and 23.24° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at diffraction angles 2 ⁇ of 7.10° ⁇ 0.2°, 8.63° ⁇ 0.2°, 11.55° ⁇ 0.2°, 12.40° ⁇ 0.2°, 16.01° ⁇ 0.2°, 17.20° ⁇ 0.2°, 17.78° ⁇ 0.2°, 18.20° ⁇ 0.2°, 20.21° ⁇ 0.2°, 21.43° ⁇ 0.2°, and 23.24° ⁇ 0.2°.
  • Form B Crystal B of the compound
  • Form B has an X-ray powder diffraction pattern substantially as shown in FIG. 3 using Cu-ka radiation.
  • thermogravimetric analysis/differential scanning calorimetry analysis diagram of Form B is substantially as shown in Figure 4.
  • the results show that Form B has a mass loss of approximately 2.24% when heated from 31°C to 120°C; the first endothermic peak appears at 43°C-90°C, which is a dehydration signal, and the second endothermic peak begins to appear around 209.6°C, which is a melting signal.
  • the X-ray powder diffraction pattern of the crystalline form B has a diffraction angle 2 ⁇ value of 5.77° ⁇ 0.2°, 8.25° ⁇ 0.2°, 11.82° ⁇ 0.2°, 13.07° ⁇ 0.2°, 14.38° ⁇ 0.2°, 15.62° ⁇ 0.2°, 16.40° ⁇ 0.2°, 17.41° ⁇ 0.2°, 17.65° ⁇ 0.2°, 18.49° ⁇ 0.2°, There are characteristic peaks at any one, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16 of 20.02° ⁇ 0.2°, 20.89° ⁇ 0.2°, 21.16° ⁇ 0.2°, 25.59° ⁇ 0.2°, 26.01° ⁇ 0.2°, and 28.83° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at diffraction angles 2 ⁇ of 5.77° ⁇ 0.2°, 13.07° ⁇ 0.2°, 16.40° ⁇ 0.2°, and 20.89° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at diffraction angles 2 ⁇ of 5.77° ⁇ 0.2°, 11.82° ⁇ 0.2°, 13.07° ⁇ 0.2°, 16.40° ⁇ 0.2°, 20.89° ⁇ 0.2° and 21.16° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at diffraction angles 2 ⁇ of 5.77° ⁇ 0.2°, 11.82° ⁇ 0.2°, 13.07° ⁇ 0.2°, 15.62° ⁇ 0.2°, 16.40° ⁇ 0.2°, 20.02° ⁇ 0.2°, 20.89° ⁇ 0.2°, 21.16° ⁇ 0.2°, 25.59° ⁇ 0.2°, and 26.01° ⁇ 0.2°.
  • Form B is a hydrate, and further, the ratio of water molecules to Compound I is non-stoichiometric.
  • Crystal D of the compound hereinafter referred to as “Crystal Form D”
  • Form D has an X-ray powder diffraction pattern substantially as shown in FIG. 9 using Cu-ka radiation.
  • Form D when heated from 31° C. to 240° C., Form D has two endothermic peaks and one exothermic peak.
  • the first endothermic peak begins to appear at 167.58° C., and there is a melting point near 176.8° C.
  • the X-ray powder diffraction pattern of the crystalline form D has diffraction angles 2 ⁇ of 4.12° ⁇ 0.2°, 5.05° ⁇ 0.2°, 8.04° ⁇ 0.2°, 9.81° ⁇ 0.2°, 11.72° ⁇ 0.2°, 13.14° ⁇ 0.2°, 14.61° ⁇ 0.2°, 15.32° ⁇ 0.2°, 15.70° ⁇ 0.2°, 16.4 There are characteristic peaks at any one, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15 of 2° ⁇ 0.2°, 18.52° ⁇ 0.2°, 19.79° ⁇ 0.2°, 21.29° ⁇ 0.2°, 22.20° ⁇ 0.2° and 25.28° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form D has characteristic peaks at diffraction angles 2 ⁇ of 5.05° ⁇ 0.2°, 11.72° ⁇ 0.2°, 14.61° ⁇ 0.2°, and 16.42° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form D has characteristic peaks at diffraction angles 2 ⁇ of 4.12° ⁇ 0.2°, 5.05° ⁇ 0.2°, 8.04° ⁇ 0.2°, 9.81° ⁇ 0.2°, 11.72° ⁇ 0.2°, 14.61° ⁇ 0.2°, 15.32° ⁇ 0.2°, 15.70° ⁇ 0.2°, 16.42° ⁇ 0.2°, 18.52° ⁇ 0.2°, and 21.29° ⁇ 0.2°.
  • Form E Crystal E of the compound
  • the X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at any one of the diffraction angles 2 ⁇ of 5.83° ⁇ 0.2°, 10.95° ⁇ 0.2°, 11.93° ⁇ 0.2°, 14.05° ⁇ 0.2°, 14.61° ⁇ 0.2°, 14.98° ⁇ 0.2°, 17.95° ⁇ 0.2°, 18.70° ⁇ 0.2°, 21.53° ⁇ 0.2°, 24.01° ⁇ 0.2°, and 25.22° ⁇ 0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11.
  • the X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at diffraction angles 2 ⁇ of 5.83° ⁇ 0.2°, 14.61° ⁇ 0.2°, 14.98° ⁇ 0.2°, 17.95° ⁇ 0.2° and 21.53° ⁇ 0.2°.
  • Form E when heated from 31° C. to 240° C., Form E has two endothermic peaks and one exothermic peak.
  • the first endothermic peak begins to appear at 187.9° C., and there is a melting point near 192.9° C.
  • Form F Crystal Form F of the compound
  • the X-ray powder diffraction pattern of the crystalline form F has characteristic peaks at any one of the diffraction angles 2 ⁇ of 5.83° ⁇ 0.2°, 10.95° ⁇ 0.2°, 11.93° ⁇ 0.2°, 14.05° ⁇ 0.2°, 14.61° ⁇ 0.2°, 14.98° ⁇ 0.2°, 17.95° ⁇ 0.2°, 18.70° ⁇ 0.2°, 21.53° ⁇ 0.2°, 24.01° ⁇ 0.2°, and 25.22° ⁇ 0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11.
  • the X-ray powder diffraction pattern of the crystalline form F has characteristic peaks at diffraction angles 2 ⁇ of 7.88° ⁇ 0.2°, 10.37° ⁇ 0.2°, 11.97° ⁇ 0.2°, 13.06° ⁇ 0.2°, 16.74° ⁇ 0.2°, 17.53° ⁇ 0.2°, and 18.54° ⁇ 0.2°.
  • the present disclosure provides a crystal O of a compound (hereinafter referred to as "form O").
  • Form O has an X-ray powder diffraction pattern substantially as shown in Figure 31 using Cu-ka radiation.
  • the DSC curve of Form O shows that Form O begins to have a melting endothermic peak at around 226.0°C and has a melting point at around 230.4°C.
  • the X-ray powder diffraction pattern of the crystalline form O has characteristic peaks at any one of the diffraction angles 2 ⁇ values of 9.24° ⁇ 0.2°, 12.00° ⁇ 0.2°, 12.31° ⁇ 0.2°, 13.44° ⁇ 0.2°, 13.95° ⁇ 0.2°, 14.22° ⁇ 0.2°, 17.23° ⁇ 0.2°, 18.90° ⁇ 0.2°, 21.15° ⁇ 0.2°, 21.55° ⁇ 0.2°, 26.26° ⁇ 0.2°, and 28.22° ⁇ 0.2°, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12.
  • the X-ray powder diffraction pattern of the crystalline form O has a characteristic peak at a 2 ⁇ value of 9.24° ⁇ 0.2°, and arbitrarily has two characteristic peaks at 2 ⁇ values of 12.00° ⁇ 0.2°, 12.31° ⁇ 0.2°, 13.95° ⁇ 0.2°, 14.22° ⁇ 0.2°, 17.23° ⁇ 0.2° and 18.90° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form O has characteristic peaks at 2 ⁇ values of 9.24° ⁇ 0.2° and 17.23° ⁇ 0.2°, and arbitrarily has one characteristic peak at 2 ⁇ values of 12.00° ⁇ 0.2°, 12.31° ⁇ 0.2°, 13.95° ⁇ 0.2°, 14.22° ⁇ 0.2° and 18.90° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form O has characteristic peaks at 2 ⁇ values of 9.24° ⁇ 0.2°, 12.00° ⁇ 0.2°, and 17.23° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form O has characteristic peaks at 2 ⁇ values of 9.24° ⁇ 0.2°, 12.00° ⁇ 0.2°, 12.31° ⁇ 0.2° and 17.23° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form O has characteristic peaks at diffraction angles 2 ⁇ of 9.24° ⁇ 0.2°, 12.00° ⁇ 0.2°, 12.31° ⁇ 0.2°, 13.95° ⁇ 0.2°, 14.22° ⁇ 0.2°, 17.23° ⁇ 0.2° and 18.90° ⁇ 0.2°.
  • the present disclosure provides an amorphous form of Compound 1.
  • the PLM image of the amorphous Compound 1 is shown in FIG33 , in which the PLM image lacks birefringence and exhibits a polygonal granular crystal habit.
  • the XRPD pattern of the amorphous form of Compound 1 is shown in Figure 32, and the X-ray powder diffraction pattern has no obvious diffraction peaks.
  • Compound 1 Amorphous Form exhibits no change in its XRPD pattern after DVS testing.
  • the present disclosure provides a pharmaceutical composition comprising a solid form of a compound of formula (I).
  • the present disclosure provides use of a solid form of Compound I in preparing a pharmaceutical preparation for treating diseases associated with PRMT5 inhibitors.
  • Form A, Form B, Form D, Form E, Form F, Form O and amorphous form have low hygroscopicity and high crystallinity while maintaining high stability, and are more suitable for pharmaceutical development.
  • Figure 1 is an XRPD pattern of Form A
  • Figure 2 is the TGA&DSC curve of Form A
  • FIG3 is an XRPD pattern of Form B
  • Figure 4 is the TGA&DSC curve of Form B
  • Figure 5 is a comparison of XRPD images of Form B before and after stability (top: heated to 120°C, bottom: before heating)
  • FIG6 is a DVS diagram of Form B
  • FIG7 is a comparison of XRPD images of Form B before and after DVS testing (top: after testing, bottom: before testing)
  • Figure 8 is a comparison of XRPD images of Form B after being placed at 25°C/92.5% RH (from top to bottom: 3 days, 2 days, and 1 day, Form B reference)
  • FIG9 is an XRPD pattern of Form D
  • Figure 10 is a comparison of XRPD images before and after the stability test of Form D (from top to bottom: heating to 218°C, heating to 120°C, Form D reference)
  • FIG11 is
  • Figure 18 is an XRPD pattern of Form L
  • Figure 19 is the TGA & DSC curve of Form L
  • Figure 20 is an XRPD pattern of Form M
  • Figure 21 is a 1 H NMR spectrum of Form M
  • Figure 22 is the TGA & DSC curve of Form M
  • Figure 23 is an XRPD pattern of Form N
  • Figure 24 is the TGA & DSC curve of Form N
  • Figure 25 is an XRPD pattern of Form P
  • Figure 26 is the TGA & DSC curve of Form P
  • FIG27 is a comparison of XRPD images of Form P before and after stability testing (from top to bottom: Form P heated to 80° C.
  • FIG30 is a comparison of XRPD images of Form Q before and after the stability test (from top to bottom; Form O, Form Q is heated to 100 degrees and transformed into Form O, Form Q (control);
  • Figure 31 is an XRPD pattern of Form O;
  • FIG32 is an XRPD pattern of amorphous form of Compound 1;
  • Figure 33 is a PLM image of the amorphous form of Compound 1;
  • FIG34 is a comparison of XRPD images of the amorphous form of Compound 1 before and after stability testing (top: after heating, bottom: before heating);
  • Figure 35 is a comparison of XRPD images of the amorphous form of Compound 1 before and after the DVS test (top: after the test, bottom: before the test).
  • XRPD patterns were obtained using a Bruker D8Advance diffractometer. Before the experiment, the voltage was set to 40 kV and the current was set to 40 mA. The sample was loaded onto a zero-background sample holder and scanned over an angle range of 2° to 40°. The scan step was set to 0.01°, and the wavelength of the X-ray used in the measurement was
  • DSC Differential scanning calorimetry experiments were performed using a Mettler-Toledo DSC3 differential scanning calorimeter (DSC). Prior to the experiment, the heating rate and melting enthalpy were calibrated using indium as a reference material. The sample was placed in a standard 40 ⁇ L aluminum crucible and then covered with a perforated lid. The weight of the sample was accurately recorded. The sample pan containing the sample was placed in the sample cavity. At the reference position, a standard 40 ⁇ L aluminum crucible was placed, which was configured in the same way as the sample pan except that it did not contain the sample. DSC measurements were performed by heating the sample from 30°C to 300°C at a heating rate of 10°C/min. Nitrogen was purged during the experiment at a flow rate of 50 mL/min.
  • TGA data were collected using a Mettler-Toledo TGA2. Prior to sample analysis, the TGA2 was calibrated with nickel. Samples were placed in an open aluminum pan, automatically weighed, and then placed in the TGA furnace. The furnace was heated from 31°C to 300°C at a heating rate of 10°C/min, with a nitrogen flow rate of 20 mL/min.
  • Moisture adsorption and desorption data were obtained using a dynamic vapor sorption instrument (Model TA Discovery SA). The sample was equilibrated at 25°C/0% RH for 300 minutes. Subsequently, the humidity level was controlled and maintained using nitrogen over a range of 0% to 95% RH in 5% RH steps. A mass change rate of less than 0.02%/min over 10 minutes was considered equilibrium during testing, with a maximum equilibration time of 120 minutes.
  • the data of the samples were collected using a Bruker 400 MHz nuclear magnetic resonance spectrometer with DMSO- d6 as the solvent.
  • room temperature is not a specific temperature value, but refers to the temperature range of 10-30°C.
  • solvate refers to a solid substance containing stoichiometric and non-stoichiometric solvent molecules (including water and organic solvents).
  • anhydrous substance refers to a solid substance that does not contain crystal water or crystallization solvent.
  • the “characteristic peak” refers to a representative diffraction peak used to identify crystals. When tested using Cu-Ka radiation, the peak position can usually have an error of ⁇ 0.2°.
  • crystal can be characterized by X-ray powder diffraction.
  • the XRPD diffraction data of the crystal has fingerprint properties. Different crystal forms are identified in the art based on the diffraction data of XRPD. Those skilled in the art will select several representative peaks in the XRPD spectrum as characteristic peaks to characterize the crystal, and will comprehensively consider the peak position, peak intensity and peak shape when selecting characteristic peaks. However, those skilled in the art will understand that the X-ray powder diffraction pattern is affected by the conditions of the instrument, the preparation of the sample and the purity of the sample.
  • the peak intensity of the diffraction peak in the X-ray powder diffraction pattern may also change with changes in the experimental conditions.
  • the peak intensity of the diffraction peak in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal.
  • the diffraction peak intensity shown in the present disclosure is illustrative and not for absolute comparison. Therefore, when identifying whether the crystal forms are the same, the matching of the peak positions within the above-mentioned error range is the first priority.
  • the X-ray powder diffraction pattern of the crystalline form or amorphous form protected by the present disclosure does not have to be completely consistent with the X-ray powder diffraction patterns in the embodiments referred to herein, and any crystalline form or amorphous form having an X-ray powder diffraction pattern that is identical or similar to the characteristic peaks in these patterns falls within the scope of the present disclosure.
  • peaks are marked in an X-ray powder diffraction pattern, it refers to any X-ray powder diffraction pattern that has an error within the range of ⁇ 0.2° from the peaks in these patterns.
  • Those skilled in the art can compare the X-ray powder diffraction patterns listed in the present disclosure with the X-ray powder diffraction patterns of an unknown crystalline form to confirm whether the two sets of patterns reflect the same or different crystalline forms.
  • the disclosed Form A, Form B, Form D, Form E, Form F, Form I, Form J, Form L, Form M, Form N, Form O, Form P, Form Q, and amorphous forms of Compound 1 are pure and substantially free of any other forms.
  • substantially free when referring to a new crystalline form or amorphous form means that the crystalline form or amorphous form contains less than 20% (by weight) of other forms, particularly less than 10% (by weight) of other forms, more particularly less than 5% (by weight) of other forms, and even more particularly less than 1% (by weight) of other forms.
  • the suspension equilibrium method involves adding an appropriate amount of solid to a specified solvent under specified conditions, ensuring the presence of undissolved solid.
  • the resulting suspension is magnetically stirred at 500 rpm in a sealed vial for 5 or 10 days at room temperature or 50°C.
  • the supernatant is then centrifuged to separate the solid, which is then vacuum-dried at 40°C for approximately 20 hours.
  • the samples were dissolved in different good solvents and filtered through a 0.22 ⁇ m nylon filter into a new sample vial.
  • Different antisolvents were slowly added dropwise to each vial under magnetic stirring, stirring until a precipitate formed. The supernatant was then removed by centrifugation to isolate the solid, which was then vacuum-dried at 40°C for approximately 20 hours.
  • the TGA&DSC curves of Form B are shown in Figure 4. The results show that there is a mass loss of about 2.24% when heated from 31°C to 120°C; the first endothermic peak appears at 43°C-90°C, which is a dehydration signal, and the second endothermic peak begins to appear around 209.6°C, which is a melting signal.
  • Form B was heated to 120°C.
  • the XRPD comparison diagrams before and after heating are shown in Figure 5. The results show that the crystal form did not change before and after heating, and Form B has good thermodynamic stability.
  • the DVS of Form B is shown in FIG6 .
  • the moisture absorption weight gain of Form B under 40-80% RH conditions is approximately 0.6%.
  • the XRPD comparison diagrams before and after the DVS test are shown in FIG7 .
  • Form B was stored at 25°C/92.5% RH for 3 days. XRPD tests were performed after 1, 2, and 3 days, respectively. The results are shown in FIG8 , indicating that Form B had no significant changes. Table 4
  • Form D When heated from 31°C to 240°C, Form D has two endothermic peaks and one exothermic peak.
  • the first endothermic peak begins to appear at 167.6°C, and the melting point is around 176.8°C.
  • Form D was heated to 120°C and 218°C at a heating rate of 10°C/min, and then cooled back to room temperature. The sample was then subjected to XRPD analysis, and the results are shown in Figure 10. Form D did not undergo transformation after being heated to 120°C. Table 5
  • Form E has characteristic peaks at 5.83° ⁇ 0.2°, 10.95° ⁇ 0.2°, 11.93° ⁇ 0.2°, 14.05° ⁇ 0.2°, 14.61° ⁇ 0.2°, 14.98° ⁇ 0.2°, 17.95° ⁇ 0.2°, 18.70° ⁇ 0.2°, 21.53° ⁇ 0.2°, 24.01° ⁇ 0.2°, and 25.22° ⁇ 0.2°.
  • Form E When heated from 31°C to 240°C, Form E has two endothermic peaks and one exothermic peak. The first endothermic peak begins to appear around 187.9°C, and the melting point is around 192.9°C.
  • Form E was heated to 226°C at a heating rate of 10°C/min, then cooled back to room temperature and tested by XRPD. The test results are shown in Figure 11. The results show that when heated to 226°C, Form E transforms into Form O.
  • Form F has characteristic peaks at 6.50° ⁇ 0.2°, 7.88° ⁇ 0.2°, 10.37° ⁇ 0.2°, 11.13° ⁇ 0.2°, 11.97° ⁇ 0.2°, 13.06° ⁇ 0.2°, 15.78° ⁇ 0.2°, 15.96° ⁇ 0.2°, 16.74° ⁇ 0.2°, 17.53° ⁇ 0.2°, 18.54° ⁇ 0.2°, and 25.45° ⁇ 0.2°.
  • Form F When heated from 31°C to 240°C, Form F has two endothermic peaks and one exothermic peak. The first endothermic peak begins to appear at 179.2°C, and the melting point is around 188.1°C.
  • TGA&DSC curve of Form I is shown in Figure 13, which shows six complex endothermic signals with onset temperatures of 40.0°C, 96.3°C, 165.3°C, 186.9°C, 212.1°C and 229.9°C, respectively; there is one exothermic peak with an onset temperature of 197.9°C.
  • the XRPD pattern of Form J is shown in FIG14 .
  • the TGA and DSC curves of Form J are shown in Figure 15.
  • the TGA results show a 2.36% weight loss from 31°C to 120°C and a 4.26% weight loss from 120°C to 160°C.
  • the DSC results show two endothermic peaks in Form J, at 99.2°C and 210.3°C, respectively.
  • the XRPD pattern of Form L is shown in FIG18 .
  • TGA and DSC curves of Form L are shown in Figure 19.
  • TGA results indicate a 9.75% mass loss upon heating from 31°C to 120°C, indicating that Form L begins to lose bound water at room temperature.
  • DSC results indicate that Form L undergoes crystal transformation and recrystallization during the dehydration process.
  • the XRPD pattern of Form M is shown in FIG20 .
  • the TGA and DSC curves of Form M are shown in Figure 22.
  • the TGA results show that the mass loss of Form M is 10.9% when heated from 31°C to 120°C. Combining the TGA and DSC results, it can be seen that Form M begins to dehydrate at a lower temperature.
  • the XRPD pattern of Form N is shown in FIG23 .
  • the XRPD pattern of Form P is shown in FIG25 .
  • the TGA & DSC curves of Form P are shown in Figure 26.
  • the TGA results show that the weight loss upon heating from 31°C to 120°C is 4.05%, which is consistent with the theoretical water content of Compound I monohydrate (4.04414% w/w).
  • Form P transforms into Form A when heated to 80°C.
  • Form P transforms into Form A below 25°C/45% RH.
  • Form Q dehydrates and crystallizes into Form O upon heating to 100° C.; on the other hand, Form Q begins to lose its crystalline water at 25° C./40% RH.
  • the DSC curve of Form O shows that Form O begins to have a melting endothermic peak at around 226.0°C and has a melting point at around 230.4°C.
  • the XRPD pattern of the amorphous form of Compound I is shown in FIG32 , and the X-ray powder diffraction pattern has no obvious diffraction peaks.
  • the PLM image of the amorphous compound I is shown in Figure 33.
  • the PLM image lacks birefringence and exhibits polygonal granular crystal habit.
  • the XRPD pattern of the amorphous form of Compound 1 did not change after the DVS test, and thus the amorphous form of Compound 1 remained unchanged after the DVS test.
  • Form A and Form O were mixed in equal amounts in a glass bottle and added to ethanol, dichloromethane, isopropyl acetate, and n-heptane that had been pre-saturated with Compound I and centrifuged. The mixture was stirred at 500 rpm at room temperature. After one day, the solid was isolated by centrifugation and characterized by XRPD. The results are shown in Table 8. The results indicate that Form A is the most thermodynamically stable form under the given solvent system and room temperature conditions. Table 8
  • Example 17 Suspension competition of Form A, Form B and Form O
  • Form A is the most thermodynamically stable form.

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Abstract

La présente divulgation concerne un solide de (S)-4-amino-N-méthyl-N- (6-(trifluorométhyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (ci-après appelé "composé I") et un procédé de préparation de celui-ci, une composition pharmaceutique contenant le composé I, ainsi qu'une utilisation du composé I dans la préparation d'un médicament inhibiteur de PRMT5.
PCT/CN2025/078952 2024-02-26 2025-02-25 Solide de composé, son procédé de préparation et son utilisation Pending WO2025180349A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999009845A1 (fr) * 1997-08-25 1999-03-04 Bristol-Myers Squibb Company Inhibiteurs a base d'imidazoquinoxalines de la proteine tyrosine kinase
WO2004085439A1 (fr) * 2003-03-27 2004-10-07 Pfizer Products Inc. 4-amino[1,2,4]triazolo[4,3-a]quinoxalines substitutees
WO2022169948A1 (fr) * 2021-02-04 2022-08-11 Amgen Inc. Inhibiteurs de prmt5 tricycliques-amido-bicycliques
WO2024037459A1 (fr) * 2022-08-18 2024-02-22 南京明德新药研发有限公司 Dérivés hétérocycliques contenant des amides et leur utilisation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999009845A1 (fr) * 1997-08-25 1999-03-04 Bristol-Myers Squibb Company Inhibiteurs a base d'imidazoquinoxalines de la proteine tyrosine kinase
WO2004085439A1 (fr) * 2003-03-27 2004-10-07 Pfizer Products Inc. 4-amino[1,2,4]triazolo[4,3-a]quinoxalines substitutees
WO2022169948A1 (fr) * 2021-02-04 2022-08-11 Amgen Inc. Inhibiteurs de prmt5 tricycliques-amido-bicycliques
WO2024037459A1 (fr) * 2022-08-18 2024-02-22 南京明德新药研发有限公司 Dérivés hétérocycliques contenant des amides et leur utilisation

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